AB0908 SCREENING AND ANALYSIS OF POSSIBLE DRUGS BINDING TO PDGFRΑ: A MOLECULAR MODELING STUDY
Authors: M. Mozzicafreddo, D. Benfaremo, C. Paolini, S. Agarbati, S. Svegliati Baroni, G. Moroncini
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The platelet-derived growth factor receptor (PDGFR) is a membrane tyrosine kinase receptor involved in several metabolic pathways, mainly in tumor progression [1, 2], immune-mediated diseases [3-4], and viral diseases [5]. <h3>Objectives</h3> Considering this macromolecule as a druggable target for modulation/inhibition of these conditions, the aim of this work was to find new ligands or new information to design novel effective drugs. <h3>Methods</h3> We performed an initial interaction screening with the human intracellular PDGFRα of about 7200 drugs and natural compounds contained in five independent databases/libraries, implemented in the MTiOpenScreen web server. After selection of 27 compounds, a structural analysis (in particular, molecular docking and molecular dynamics analysis, using SwissDock based on EADock DSS algorithm [6, 7] and GROMACS [8], respectively) of the complexes obtained was performed. Three-dimensional quantitative structure–activity relationship and ADMET analyses were also performed to understand physicochemical properties of that compound to increase affinity and selectivity. <h3>Results</h3> Among these 27 compounds, the drugs Bafetinib, Radotinib, Flumatinib and Imatinib showed the higher affinity for this tyrosine kinase receptor, lying in the nanomolar order, while the natural products, such as curcumin, luteolin and EGCG, included in this group showed submicromolar affinities. All these compounds, through the QSAR and ADMET analysis, provided physicochemical information about an ideal best ligand for PDGFRα. <h3>Conclusion</h3> Although experimental studies are recommended, the structural information obtained could provide useful insight into the future development of PDGFRα inhibitors. <h3>References</h3> [1]Winger JA, Hantschel O, Superti-Furga G, Kuriyan J. The structure of the leukemia drug imatinib bound to human quinone reductase 2 (NQO2). BMC Struct Biol. 2009 Feb 24; 9:7. [2]Salem MSH, Abdel Aziz YM, Elgawish MS, Said MM, Abouzid KAM. Design, synthesis, biological evaluation and molecular modeling study of new thieno[2,3-d]pyrimidines with anti-proliferative activity on pancreatic cancer cell lines. Bioorg Chem. 2020 Jan; 94:103472. [3]Paolini C, Agarbati S, Benfaremo D, Mozzicafreddo M, Svegliati S, Moroncini G. PDGF/PDGFR: A Possible Molecular Target in Scleroderma Fibrosis. Int J Mol Sci. 2022 Mar 31; 23(7). [4]Moroncini G, Grieco A, Nacci G, Paolini C, Tonnini C, Pozniak KN, et al. Epitope Specificity Determines Pathogenicity and Detectability of Anti-Platelet-Derived Growth Factor Receptor alpha Autoantibodies in Systemic Sclerosis. Arthritis Rheumatol. 2015 Jul; 67(7):1891-1903. [5]Grzesk G, Wozniak-Wisniewska A, Blazejewski J, Gorny B, Wolowiec L, Rogowicz D, et al. The Interactions of Nintedanib and Oral Anticoagulants-Molecular Mechanisms and Clinical Implications. Int J Mol Sci. 2020 Dec 30; 22(1). [6]Grosdidier A, Zoete V, Michielin O. SwissDock, a protein-small molecule docking web service based on EADock DSS. Nucleic Acids Res. 2011 Jul; 39(Web Server issue):W270-277. [7]Grosdidier A, Zoete V, Michielin O. Fast docking using the CHARMM force field with EADock DSS. J Comput Chem. 2011 Jul 30; 32(10):2149-2159. [8]Van Der Spoel D, Lindahl E, Hess B, Groenhof G, Mark AE, Berendsen HJ. GROMACS: fast, flexible, and free. J Comput Chem. 2005 Dec; 26(16):1701-1718. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.